CRISPR/Cas9 editing of NKG2A improves the efficacy of primary CD33-directed chimeric antigen receptor natural killer cells
Chimeric antigen receptor (CAR)-modified natural killer (NK) cells show antileukemic activity against acute myeloid leukemia (AML) in vivo. However, NK cell-mediated tumor killing is often impaired by the interaction between human leukocyte antigen (HLA)-E and the inhibitory receptor, NKG2A. Here, we describe a strategy that overcomes CAR-NK cell inhibition mediated by the HLA-E-NKG2A immune checkpoint. We generate CD33-specific, AML-targeted CAR-NK cells (CAR33) combined with CRISPR/Cas9-based gene disruption of the NKG2A-encoding KLRC1 gene. Using single-cell multi-omics analyses, we identified transcriptional features of activation and maturation in CAR33-KLRC1<sup>ko</sup>-NK cells, which are preserved following exposure to AML cells. Moreover, CAR33-KLRC1<sup>ko</sup>-NK cells demonstrate potent antileukemic killing activity against AML cell lines and primary blasts in vitro and in vivo. We thus conclude that NKG2A-deficient CAR-NK cells have the potential to bypass immune suppression in AML.
Authors
- Leon Buchinger
- Thomas Oellerich (ORCID: https://orcid.org/0000-0001-6570-6125)
- Alec Geßner
- Vinzenz Särchen (ORCID: https://orcid.org/0000-0001-9565-2850)
- Evelyn Ullrich (ORCID: https://orcid.org/0000-0001-8530-1192)
- Nawid Albinger (ORCID: https://orcid.org/0000-0003-2989-4020)
- Jan‐Henning Klusmann (ORCID: https://orcid.org/0000-0002-1070-0727)
- Hadeer Mohamed Rasheed (ORCID: https://orcid.org/0000-0003-1010-296X)
- Michael A. Rieger (ORCID: https://orcid.org/0000-0002-4158-5872)
- Sebastian Wolf (ORCID: https://orcid.org/0000-0001-5298-8901)
- Raj Bhayadia (ORCID: https://orcid.org/0000-0003-0865-9582)
- Nina Möker
- Jamal Alzubi (ORCID: https://orcid.org/0000-0003-4284-2006)
- Tobias Bexte (ORCID: https://orcid.org/0009-0009-2392-6416)
- Olaf Penack (ORCID: https://orcid.org/0000-0003-4876-802X)
- Philipp Wendel (ORCID: https://orcid.org/0000-0001-5844-1587)
- Meike Vogler (ORCID: https://orcid.org/0000-0003-2650-586X)
- Toni Cathomen (ORCID: https://orcid.org/0000-0002-7757-4630)
- Katharina Imkeller
- Ahmad Al Ajami (ORCID: https://orcid.org/0009-0006-5615-7447)
- Beate Anahita Jung
Institutions
- Goethe University Frankfurt (DE)
- Miltenyi Biotec (Germany) (DE)
- University of Freiburg (DE)
- German Cancer Research Center (DE)
- Heidelberg University (DE)
- German Red Cross (DE)
- Technische Universität Darmstadt (DE)
- Humboldt-Universität zu Berlin (DE)
- German Cancer Society (DE)
- University Hospital Frankfurt (DE)
- Cardio-Pulmonary Institute (DE)
- Frankfurt Cancer Institute (DE)
- Deutsches Konsortium für Translationale Krebsforschung (DE)
- Alexandria University (EG)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-09-30
- DOI
- https://doi.org/10.1038/s41467-024-52388-1
- Citations
- 61
- Primary Topic
- Immune Cell Function and Interaction
- Type
- article
- Field-Weighted Citation Impact
- 14.67